Targeting fibroblast derived thrombospondin 2 disrupts an immune-exclusionary environment at the tumor front in colorectal cancer
Fibrotic colorectal cancers (CRC) are largely microsatellite-stable and display desmoplastic stroma with poor immune infiltration. Here we identify thrombospondin-2 (THBS2) as a key regulator of the immune-exclusionary phenotype in fibrotic CRC. THBS2 is highly expressed by matrix cancer-associated fibroblasts at the tumor front. In an orthotopic model using desmoplastic tumor organoids, global or fibroblast-specific Thbs2 deletion disrupts the exclusionary barrier and increases intratumoral CD8 T cells. Mechanistically, THBS2 limits recruitment of CXCR3<sup>+</sup> CD8 T cells by restraining dendritic- and macrophage-derived CXCL9/10. Depletion of these myeloid cells or blockade of CXCL9/10-CXCR3 signaling abolishes the enhanced CD8 T-cell influx and antitumor efficacy. Spatial profiling demonstrates that THBS2 loss induces proximity between CD8 T cells and myeloid cells and upregulates chemokines. Despite increased infiltration, CD8 T cells manifest exhaustion, rendering tumors highly susceptible to immune checkpoint blockade. THBS2 thus represents a tractable CAF-restricted target to overcome immune exclusion in fibrotic CRCs.
Authors
- María T. Díaz‐Meco (ORCID: https://orcid.org/0000-0003-0147-0998)
- Hiroshi Seno (ORCID: https://orcid.org/0000-0002-8509-8128)
- Kiyoshi Maeda
- Yoko Masui
- Yukiko Hiramatsu (ORCID: https://orcid.org/0000-0001-5903-8677)
- Yukina Kusunoki (ORCID: https://orcid.org/0009-0002-4257-729X)
- Mayuki Omatsu (ORCID: https://orcid.org/0000-0003-1595-7094)
- Akihisa Fukuda (ORCID: https://orcid.org/0009-0005-2215-681X)
- Masakazu Fujimoto (ORCID: https://orcid.org/0000-0002-0575-6507)
- Munenori Kawai (ORCID: https://orcid.org/0000-0001-9784-1487)
- Kenji Kabashima (ORCID: https://orcid.org/0000-0002-0773-0554)
- Masakazu Yashiro
- Takahisa Maruno (ORCID: https://orcid.org/0000-0002-7060-4104)
- Yasuhiro Fukui (ORCID: https://orcid.org/0000-0001-8878-883X)
- Yuki Nakanishi (ORCID: https://orcid.org/0000-0001-5493-6312)
- Jorge Moscat (ORCID: https://orcid.org/0000-0002-9442-3834)
- Yoshiro Itatani (ORCID: https://orcid.org/0000-0001-7356-7065)
- Nobukazu Agatsuma (ORCID: https://orcid.org/0000-0002-4605-5985)
- Shinnosuke Nakayama (ORCID: https://orcid.org/0000-0002-1048-1202)
- Kenta Mizukoshi (ORCID: https://orcid.org/0000-0002-0847-154X)
- Kazutaka Obama (ORCID: https://orcid.org/0000-0003-2924-6701)
- Liyang Cai
- Toshiaki Kogame (ORCID: https://orcid.org/0000-0002-0683-719X)
- Nobuyuki Kakiuchi (ORCID: https://orcid.org/0000-0003-4893-5414)
- Masahiro Nakagawa (ORCID: https://orcid.org/0000-0002-6420-2555)
- Naoki Aoyama (ORCID: https://orcid.org/0000-0003-3978-2778)
- Munehiro Ikeda (ORCID: https://orcid.org/0000-0002-9117-3702)
- Seishi Ogawa (ORCID: https://orcid.org/0000-0002-7778-5374)
- Takahiro Utsumi (ORCID: https://orcid.org/0000-0001-6067-3694)
- Kei Iimori (ORCID: https://orcid.org/0000-0002-9252-755X)
- KOICHI YASUMURA
- Kensuke Hamada (ORCID: https://orcid.org/0000-0002-8965-7302)
- Yu Muta (ORCID: https://orcid.org/0000-0001-5311-363X)
- Munemasa Nagao (ORCID: https://orcid.org/0000-0003-0789-6623)
- Hiroaki Kasashima (ORCID: https://orcid.org/0000-0001-5234-4030)
- Kosuke Iwane
- Jiayu Chen (ORCID: https://orcid.org/0000-0003-4755-8901)
- Go Yamakawa
Institutions
- Cornell University (US)
- Kyoto University (JP)
- Kyoto University Hospital (JP)
- Weill Cornell Medicine (US)
- Tokyo Metropolitan University (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-23
- DOI
- https://doi.org/10.1038/s41467-025-66485-2
- Citations
- 1
- Primary Topic
- Angiogenesis and VEGF in Cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.81